Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It often resists treatment, frequently returns, and spreads quickly. Despite years of research, fewer than 10% of patients live beyond five years after diagnosis, and more than 80% die from its spread within two years.
For PDAC to spread, it must break through blood vessel walls, a key step that scientists still don’t fully understand. While many studies have explored TGFβ receptors in cancer, one specific receptor, ALK7, hasn’t been studied extensively, and its role in the spread of PDAC has remained unclear.
A Cornell-led study has cracked a long-standing mystery in cancer biology: how pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, manages to spread so efficiently despite being encased in a dense, fibrotic armor that should, in theory, keep it contained.
Published in Molecular Cancer, the research identifies a biological receptor called ALK7 as the key enabler of metastasis. This receptor activates two powerful pathways: one that boosts cancer cell mobility via epithelial-mesenchymal transition, and another that produces enzymes capable of breaking down blood vessel walls.
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Esak Lee, lead author of the study and assistant professor in the Meinig School of Biomedical Engineering in Cornell Engineering, said, “In other words, ALK7 gives pancreatic cancer cells both the engine to move and the tools to invade.”
PDAC’s paradoxical behavior, its ability to metastasize despite a seemingly impenetrable microenvironment, has long baffled scientists. The tumor’s fibrotic shell makes drug delivery difficult and should act as a physical barrier. Yet, patients often face rapid disease spread, with fewer than 10% surviving five years post-diagnosis.
To unravel this, Lee’s team used mouse models and a cutting-edge organ-on-chip system developed in his lab. This system mimics human blood vessels, allowing researchers to study cancer progression in a controlled, human-like environment.
Their experiments revealed that blocking ALK7 significantly slowed the cancer’s ability to metastasize. Crucially, the timing of intervention mattered. When ALK7 was inhibited early, before cancer cells entered the bloodstream, metastasis was halted. But once cells were already circulating, they spread rapidly.
“Once we miss this early opportunity to block ALK7 receptors, the cancer cells can freely circulate in the bloodstream and easily seed into other organs,” Lee explained. “But if we can inhibit ALK7 at the cancer’s earliest and most vulnerable stage, we might see better outcomes for patients.”
The study also helps reconcile conflicting reports about ALK7’s role, with some suggesting it suppresses cancer spread and others indicating it promotes it. Lee’s findings suggest that ALK7’s impact may vary depending on the type and stage of the cancer.
Beyond PDAC, the organ-on-chip platform opens new possibilities for studying other cancers and immune cell behavior.
“Some cancers have very different microenvironments, so, potentially, ALK7 might show different impacts,” Lee said. “I hope this study really opens a new avenue for cancer research.”
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The work was supported by the National Institutes of Health, National Science Foundation, and the National Research Foundation of Korea.
Journal Reference:
- Kolarzyk, A.M., Kwon, Y., Oh, E. et al. Non-canonical ALK7 pathways promote pancreatic cancer metastasis through β-catenin/MMP-mediated basement membrane breakdown and intravasation. Mol Cancer 24, 188 (2025). DOI: 10.1186/s12943-025-02384-w
